Deep vein thrombosis (DVT) and pulmonary embolism (PE), collectively referred to as venous thromboembolism (VTE), is the third most common cause of vascular death in the US, after only heart attacks and strokes. Current data suggest that genetic factors contribute to > 60% of VTE risk. However, known common variants, confirmed in recent genome-wide association studies (GWAS), such as Factor V Leiden and the ABO blood group, account for only half of this risk. The remaining genetic determinants for VTE are yet to be determined but may involve a combination of common polymorphisms, rare mutations and structural genomic variants. In preliminary studies, we have completed the exome sequencing of 8 individuals with unprovoked VTE. By focusing on 27 genes corresponding to known coagulation, fibrinolytic, and VTE gene networks, we identified 13 heterozygous mutations at 8 loci. Additionally, we investigated the genetic determinants of plasma von Willebrand Factor (VWF), a plasma protein with an established effect on thrombosis risk, by genotyping and measuring VWF levels in 3384 individuals, in 579 sibships from the Genes and Blood Clotting Study (Ginsburg, Desch, University of Michigan) and the Trinity Student Study (Brody, Malloy, NHGRI and Trinity College, Ireland). Our GWAS of VWF antigen levels confirm ABO and VWF as the major common loci regulating plasma VWF with 4 additional novel loci identified by linkage analysis that were undetected by GWAS. Aim 1 of this proposal will extend the study of this cohort to other potential modifiers of thrombosis risk such as FV, FVIII, plasminogen, PAI-1, D-dimer, antithrombin III, Protein S, and Protein C. Aim II and III focus on analysis of a cohort of VTE patients in order to adequately address the potential contribution of rare variants influencing VTE risk. We propose to perform whole exome sequencing in a discovery group of 250 patients with unprovoked VTE and compare the identified mutation patterns with those in controls. Loci with significant clustering of rare variats will be analyzed by targeted resequencing and/or genotyping in a larger replication cohort. DNA samples for analysis will be drawn from established cohorts in collaboration with the GIFT Study (Visser and Reitsma, Leiden University, NL) and the ELATE and DODS cohorts (Kearon, McMaster, Canada). We have assembled an experienced, integrated team of investigators from several disciplines such as experimental genomics, statistical genetics, coagulation and thrombosis biology, medical genetics and clinical care. The results should significantly advance our understanding of the genetic basis of VTE pathogenesis and enhance our capacity to identify patients at high risk for VTE. PUBLIC HEALTH RELEVANCE: Venous Thromboembolic Disease (VTE) is a clinically important problem. Genetic risk for VTE is a complex genetic trait involving multiple genes and environmental interactions. This proposal uses state of the art genetic techniques to uncover novel genetic risk factors affecting VTE risk.